Solubilizer for preparing an aqueous soluble menadione



United States Patent Ofiice 2,808,361" Patented Oct. 1, 1957 SOLUBILIZERFOR PREPARING AN AQUEOUS SOLUBLE MENADIONE Russell R. Bavouset,Pasadena, Calif.

No Drawing. Application March 9, 1955, Serial No. 493,309

Claims. (Cl. 167-81) necessity for adminismuscular absorption. used inisotonic dextrose solutions for slow intravenous administration.Further, if rendered water-soluble, it is subject to oral administrationwithout requiring concurrent administration of bile salts to make thevitamin K activity available.

I have discovered that menadione can be solubilized and stabilized byincorporating it in an aqueous solutron of nicotinamide, and that itthen becomes useful for the above indicated purposes. Such solubiliziugavoids the requirement for fat-solubilization by reason of bile flow,and bile-flow obstmction does not therefore I become a deterent to thestituent.

The usual dose of menadione is one or two milligrams daily. I havediscovered that one (1) milligram of menadione may be solubilized andstabilized with one hundred (100) milligrams of nicotinamide, and thattwo (2) milligrams of menadione are readily solubilized with one hundredfifty (150) milligrams of nicotinamide. The nicotinamide is desirablyused as a 33% aqueous solution (weight basis), that is 50 grams in 100milliliters of water, but concentrations between about grams to 100grams of nicotinamide in 100 milliliters of water may be used, or about15% to solutions. Since menadione is decomposed by sunlight, it isimportant to protect it from light at all times. This is accomplished,for example, by agitation or stirring of the menadione into the aqueousnicotinamide solution in a bottle or other vessel, such as a small neckflask, capable of sufliciently retarding or excluding light passage.This condition may be attained by using brown glass vessels. Also airshould be excluded as much as possible as by working in a carbon dioxideatmosphere, whereby to avoid oxidation. Avoidance of oxidation andmaintaining the characteristic light yellow color of the solution isthus easily accomplished. Production of the solution is efiected atordinary room temperatures around 70 R, or between about F. and 110 F.,or a little higher, but temperatures above about 180 F., or especiallyat the boiling point of water, should be avoided to avoid discolorationand oxidation. Stabilization and oxidation control may be assisted byemploying use of the vitamin K conbe readily accepted by the patientwithvitamin C, as presently to be described. After producing thesolution, such concentrations as required will be obtained by dilution,packaging of such as ampuling being then eifected.

Since nicotinamide is itself a desirable vitamin, being one of the Bcomplex and the pellagra-prevention factor, and since the daily dose isin the order of the above mentioned to milligrams, it is a mostdesirable agent to be employed with the K vitamin constituent inaccordance with this invention. Other vitamins may be added as may bedesirable for different purposes, such as riboflavin, thiamine, andother water-soluble members of the B complex.

The overall permissible and practical range of proportions ofnicotinamide which may be used in solubilizing menadione is from aminimum of about 100 milligrams per milligram of menadione up tothathigher amount required for the maximum therapeutic effect desired fromthe nicotinamide.

Since menadione, which is a synthetic naphthoquinone derivative, iswater-insoluble, although soluble in alcohol, benzene, vegetable oilsand the like, but possesses the desirable properties of vitamin K, andsince nicotinamide which is water-soluble is both a valuable vitamin anda solubilizer for menadione, it is apparent that I have presented avaluable improvement in the present aqueous solution of menadioneemploying nicotinamide.

The aqueous solution of this invention, being acceptable for parenteralinjection, has many advantages over oil solutions of menadione, inasmuchas many patients are allergic to oil injections, the oil solution isslowly absorbed, the present water solution is rapidly absorbed andtherefore quickly available for utilization in the human body, and inaddition this aqueous solution can be used for intravenous injections inemergencies whereas the oil solutions can never be used intravenously.

Also, by means of this improvement, it is possible to employ in aqueoussolution the solubilized vitamin K in combination with otherwater-soluble vitamins than nicotinamide, such as other members of the Bcomplex, and employ such a solution of multiple vitamins for parenteraland intravenous injections in preoperative treatment to guard againsthemorrhage and fortify against periods of stress.

Another advantage of my discovery is its value for oral use when theflow of bile has been obstructed. Ordinarily some of the fat-solublevitamins, including vitamin K and menadione, are not absorbed in theabsence of bile flow unless bile salts are administered. Here thewater-soluble vitamin K requires no bile or bile salts. This is veryimportant because menadione is extraordinarily effective againsthemorrhagic diaphesis of obstructive jaundice. It provides the vitamin Krequired for the liver to synthesize prothrombin, which is essential inthe blood stream, but would be deficient in the event of bileobstruction if only oil-soluble vitamin K were supplied. When vitamin Kas such is mentioned, it is in general intended to signify K1 and K2.

With respect to the employment of other vitamins, another phase of thisinvention is the use of vitamin C, because, in addition to its normalvitamin function, it serves to stabilize the menadione solution againstdiscoloration and other oxidation evidences such as precipitation, whichmay render the menadione-nicotinamide solution unsuitable for parenteralinjection. Such condition may be due to hydrolysis with subsequentoxidation of the liberated hydroquinone. This hydrolysis is prevented bythe strong antioxidant properties of vitamin C, either as ascorbic acidor as the sodium salt thereof where a neutral solution is required, andwhich is to be considered as the equivalent when vitamin C or ascorbicacid is mentioned.

The vitamin C may be incorporated in the solution above described in anyappropriate manner, a desirable means being the addition of a 10%solution to the menaiPR? lllt qn but i m be a de as a Weaker or treasesolution 9 ind fo m i In general, 100 milligrams of ascorbic acid willbe used for each 100 milligrams of nicotinamide and one milligram ofmenadione, but the proportion may be varied between about 50 and 200milligrams of ascorbic acid (or sodium ascorbate). In fact, if only theantioxidant property is required, as little as about milligrams ofvitamin C may be used for each milligram of menadione {to stabilise thesame, whereas about 100 milligrams of nicotinamide is used to solubilizeone milligram of menadione. In the case of both nicotinamide and vitaminC, the amounts may be increased up to 200 milligrams or more for eachmilligram of menadione, if desired for requires! h ra u i effects.

I Specific usable formulas, depending upon elfects desired, include thefollowing:

Example 1 Each milliliter of water solution contains:

Milligrams Menadione 0.1 Nicotinamide t 10.0 Ascorbic acid 10.0 Example11 Each milliliter of water solution contains:

Milligrams Menadione 0.5 Nicotinamide a 50.0 Ascorbic acid 50.0 Example111 Each milliliter of water solution contains:

Milligrams Menadione 2.0 Nicotinamide 200.0 Ascorbic acid 100.0

The overall range of nicotinamide and vitamin C with respect tomenadione is represented by the following table which also isrepresentative of an average desirable menadione concentration in onemilliliter of water as a dose:

Milligrams Menadione Nicotinamide 100 to 200 Ascorbic acid 5 to 200While it is generally important, sometimes the ascorbic acid (or sodiumascorbate) may be entirely omitted from the above examples, as whenstorage periods and other conditions are such that objectionablediscoloration, oxidation or precipitation does not occur to render thesolution unusable for parenteral injection. Fresh preparation by thephysician from the dry ingredients near the time of administrationrepresents one such situation.

I claim:

1. A water solution of nicotinamide having dissolved therein a greaterquantity of menadione than can be dissolved in an equal quantity ofwater alone.

2. A Water solution of nicotinamide having dissolved therein at leastabout 0.5 mg. of menadione per ml. of solution.

3. An aqueous therapeutic solution having dissolved therein from about0.5 mg. to about 2 mg. of menadione and from about mg. to about 200 mg.of nicotinamide per ml. of solution.

4. An aqueous therapeutic solution as defined in claim 3 wherein saidsolution also contains about 5 to 200 mg. of ascorbic acid per ml. ofsolution.

5. An aqueous therapeutic solution having dissolved therein about 1 mg.of menadione, about mg. of nicotinamide, and about 100 mg. of ascorbicacid per ml. of solution.

References Cited in the file of this patent Modern Drugs, October 1950,p. 466.

3. AN AQUEOUS THERAPEUTIC SOLUTION HAVING DISSOLVED THEREIN FROM ABOUT0.5 MG. TO ABOUT 2 MG. OF MENADIONE AND FROM ABOUT 50 MG. TO ABOUT 200MG. OF NICOTINAMIDE PER ML. OF SOLUTION.